# Transcriptional regulation of cardiac conduction system morphogenesis

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $671,515

## Abstract

PROJECT SUMMARY/ABSTRACT
The propagation of electrical impulses that coordinate the rhythmic and synchronized cardiac contractions to
facilitate systemic circulation is regulated by a specialized structures and cell types, the cardiac conduction
system (CCS), and working cardiomyocytes in a spatial-temporally precise manner. Congenital defects of the
CCS and dysregulation of CCS homeostasis can lead to CCS dysfunction, causing life threatening
arrhythmias and increasing the risk of death in both children and adults. Genome Wide Association studies
(GWAS) in human patients with various arrhythmias have revealed a close association between abnormal
ECG and many ion channels, gap junction proteins, muscle structural proteins as well as a number of critical
transcription factors that function in cardiac development and the specification, differentiation and homeostatic
maintenance of the CCS, among them include the basic Helix-loop-Helix (bHLH) transcription factor Hand1
and the T-box transcription factor Tbx20. Hand1 is expressed in the early developing hearts and is essential
for cardiac morphogenesis. Tbx20 is shown to be critically involved in multiple cardiogenic events and cardiac
function. Interestingly, despite Hand1 and Tbx20 are not previously associated with roles in CCS development
or function, GWAS analysis revealed single nucleotide polymorphisms (SNPs) within both HAND1 and TBX20
associated with prolonged QRS duration with strong linkage disequilibrium. For both HAND1 and TBX20
these SNPs are intergenic suggesting roles in transcriptional regulation of these genes. Indeed, we have
identified a left ventricle (LV) Hand1 enhancer with GATA4 and T-box binding sites that resides within a
conserved non-coding sequence (CNS) that lies in between the reported SNPs. Mutant mice that have
harbored a gene-edited deletion of this enhancer result in a prolonged QRS. Supporting this finding, we have
recently observed that Hand1 is specifically expressed within CCS structures in postnatal hearts.
Transcriptional regulation of Tbx20 is expressed in multiple cardiac cell lineages. Myocardial gain- or loss-of-
function studies have shown altered QRS duration and severe arrhythmia. Collectively, our overriding
hypothesis is that Hand1 and Tbx20 coordinate and maintain the spatial and temporal control of the cardiac
conductive system development and function via either parallel or single gene regulatory pathways. We will
test this hypothesis with the following specific Aims: 1) to test the hypothesis that adult expression of Hand1
within the CCS is required for maintaining a normal QRS duration; 2) to test the hypothesis that Tbx20
functions in the development and homeostasis of the CCS as well as the maintenance of the conductive
function of cardiomyocytes; 3) to test whether Hand1 and Tbx20 serves as key transcriptional regulators for
CCS development and CCS physiological function in a common or different regulatory pathways.

## Key facts

- **NIH application ID:** 10428346
- **Project number:** 5R01HL145060-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Anthony B. Firulli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $671,515
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428346

## Citation

> US National Institutes of Health, RePORTER application 10428346, Transcriptional regulation of cardiac conduction system morphogenesis (5R01HL145060-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10428346. Licensed CC0.

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